Depression

Memories Linked to Social Defeat Can Hijack the Hippocampus

Inhibiting negative memory storage could be a future treatment for depression.

Posted Aug 12, 2019

Negative memories associated with social defeat are more likely to take hold and "stick" to a web of neurons in some brains than others, according to a new study (Zhang et al., 2019) in mice. This web of neurons is called an "engram."

What is a memory engram? In the early-20th century, the concept of neural networks creating a memory engram was pioneered by Richard Semon (1859-1918). Semon coined the term engram (or "memory traces") as a way to represent an assembly of neurons associated with specific memories that were formed after encountering a stimulus or stressor.

The engram concept stemmed from Semon's theory of memory and is rooted in his notion of "psychophysiological parallelism" between external-to-internal experiences; he hypothesized that psychological states corresponded directly to changes in the nervous system. Today, it is widely accepted that subgroups of neurons in the hippocampus are activated by experience and that so-called "engrams" hold specific memories.

 10.1523/JNEUROSCI.1958-18.2019)
Fluorescent-tagged cells in the hippocampus (A), including engram cells (D).
Source: Zhang et al., JNeurosci 2019 (DOI: 10.1523/JNEUROSCI.1958-18.2019)

In their recent study, "Negative Memory Engrams in the Hippocampus Enhance the Susceptibility to Chronic Social Defeat Stress," researchers from the Douglas Hospital Research Centre at McGill University tagged hippocampal engrams that formed after mice had experienced social stress and examined their subsequent behavior. These findings were published August 12 in the Journal of Neuroscience.

For this study, researchers used the chronic social defeat stress (CSDS) model to examine social defeat-related engrams in the hippocampus of mice that were either susceptible or resilient to a social defeat stressor. As the authors explain, "The CSDS model allows us to separate mice according to their individual differences in stress susceptibility. We found that mice that were susceptible to CSDS had more social defeat-related engram cells in the hippocampal CA1 region than non-stressed control mice and mice that were resilient to this stressor."

Although this study was conducted using a mouse model, senior author Tak Pan Wong and colleagues speculate that negative memories held in the hippocampus could underlie some of the cognitive symptoms associated with depression in humans. Wong is an associate professor in the Department of Psychiatry at McGill University.

Interestingly, although all of the mice in this study were exposed to the same stressor, only some mice displayed behaviors associated with cognitive symptoms of depression; these depression-prone mice also had higher concentrations of negative memory engrams in the hippocampus than mice who were resilient to depressive symptoms.

The authors sum up the importance of their findings in a significance statement:

"We provided evidence that negative memory hippocampal engrams contribute to the susceptibility to developing depression-related behavior after chronic social defeat stress. The activation of positive memory engrams have been shown to alleviate depression-related behaviors, while our findings reveal the pathological roles of negative memory engrams that could lead to those behaviors. Increased negative memory engrams could be a downstream effect of the reported high hippocampal activity in animal models and patients with depression."

Tian Rui Zhang et al. (2019) found that the density of negative memory engram cells in the hippocampus of mice correlated directly with the degree of social avoidance behavior. This discovery may help to explain the neurobiological underpinnings that put some of us at higher risk for developing depression.

The promising news: Suppressing negative memory engram cells in mice decreased social avoidance behaviors—this suggests that targeting these neurons in the hippocampus could lead to previously unexplored depression treatments in the future. Of course, more research is needed, but these preliminary findings might represent the first step towards an entirely new route for treating major depressive disorder (MDD).

References

Tian Rui Zhang, Amanda Larosa, Marie-Eve Di Raddo, Vanessa Wong, Alice S. Wong, and Tak Pan Wong. "Negative Memory Engrams in the Hippocampus Enhance the Susceptibility to Chronic Social Defeat Stress." Journal of Neuroscience (First published: August 12, 2019) DOI: 10.1523/JNEUROSCI.1958-18.2019